This invention belongs to the fields of pharmaceutical chemistry and synthetic organic chemistry, and provides processes and key intermediates for the synthesis of N-[propionyl]-5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine, a selective 5-HT.sub.1F agonist.
Serotonin (5-HT) exhibits diverse physiological activity mediated by at least seven receptor classes, the most heterogeneous of which appears to be 5-HT.sub.1. A human gene which expresses one of these 5-HT.sub.1 receptor subtypes, named 5-HT.sub.1F, was isolated by Kao and coworkers (Proc. Natl. Acad. Sci. USA, 90, 408-412 (1993)). This 5-HT.sub.1F receptor exhibits a pharmacological profile distinct from any serotonergic receptor yet described.
Moskowitz has proposed that currently unknown triggers for pain stimulate trigeminal ganglia which innervate vasculature within the cephalic tissue, giving rise to release of vasoactive neuropeptides from axons on the vasculature. These released neuropeptides then activate a series of events, a consequence of which is pain. This neurogenic inflammation is blocked by sumatriptan and ergot alkaloids by mechanisms involving 5-HT receptors, believed to be closely related to the 5-HT.sub.1D subtype, located on the trigeminovascular fibers (Neurology, 43(suppl. 3), S16-S20 (1993)). It has been demonstrated that agonists of the 5-HT.sub.1F receptor inhibit peptide extravasation due to stimulation of the trigeminal ganglia (Audia and Nissen, U.S. Pat. No. 5,521,196).
Compounds which exhibit affinity for the 5-HT.sub.1F receptor provide a new approach for the treatment of diseases linked to abnormal serotonergic neurotransmission. Furthermore, compounds selective for the 5-HT.sub.1F receptor subtype are potentially useful for treating such diseases while causing fewer undesired side effects. N-[propionyl]-5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine is a selective 5-HT.sub.1F agonist which may be prepared by acylation of 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine.